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At least 109 records · Page 6Linked to original sources
PubMed1995

Diarrhoea in HIV-infected patients: no evidence of cytokine-mediated inflammation in jejunal mucosa.

OBJECTIVE: To determine whether a mucosal cytokine-mediated inflammatory response is involved in cryptosporidial or microsporidial diarrhoea, as well as in diarrhoea of unknown origin in HIV-infected patients. DESIGN: Prospective study. METHODS: Jejunal biopsies were obtained from HIV-infected patients with diarrhoea. Controls were HIV-infected and HIV-seronegative patients without diarrhoea. Two biopsies were homogenized immediately and two other biopsies were first cultured for 20 h. Cytokines [tumour necrosis factor (TNF), interleukin (IL)-1 beta, IL-6, IL-8, IL-10], soluble TNF receptors (sTNFR) p55 and p75, and soluble IL-2 receptor (sIL-2R) were assessed in the homogenates and in the supernatants by sandwich enzyme-linked immunosorbent or enzyme-linked binding assays. The cytokine receptors were also measured in serum. RESULTS: Six HIV-infected patients with cryptosporidiosis, six with microsporidiosis, seven with diarrhoea of unknown origin, seven without diarrhoea, and seven HIV-seronegative patients were eligible. Four patients were excluded because of the presence of other pathogens. No cytokines were detected in immediately homogenized jejunal tissue. Following culture, IL-6 and IL-8 levels were higher in HIV-infected patients with diarrhoea of unknown origin than in HIV-seronegative controls without diarrhoea, although this was not statistically significant. No differences in serum or post-culture supernatant sTNFR p55 and p75 levels existed between the HIV-infected patients with or without diarrhoea. sTNFR, IL-1 beta, IL-10 and the sIL-2R were only detected in low amounts or not at all, and were equally distributed among all patient groups. CONCLUSIONS: This study indicates that mucosal cytokine-mediated inflammatory responses do not play an important role in the pathogenesis of different types of diarrhoea in HIV-infected patients. These results do not support the use of immunomodulatory therapy in these patients.

AIDS-Related Opportunistic Infections↗
PubMed1989

IL-1 dependent model of inflammation mediated by neutrophils.

Interleukin-1 (IL-1) mediates a number of immunologic and physiologic responses associated with inflammation. A new model to monitor the primary effects of IL-1 and potential inhibitors on inflammation has been developed, which involves unilateral injection of 300 U of highly purified recombinant human IL-1 in mouse ears. Ear thickness of IL-1 injected ears increased 7-10-fold 24 hr posttreatment, concomitant with a corresponding increase in myeloperoxidase activity, suggesting that neutrophil influx contributes to this response. Administration of nonsteroidal antiinflammatory drugs did not influence the IL-1 effect in vivo. Inhibition of phospholipase A2 activity ameliorated the IL-1 stimulated inflammation; treatment with 10 mg/kg dexamethaxone eliminated approximately 80% of increased myeloperoxidase activity compared to control values. This model provides a well-defined in vivo assay with which to quantify the systemic effects of compounds capable of altering the activity of IL-1, and the data suggest that this mechanism may explain the unique efficacy of steroids as antiinflammatories.

Animals↗
PubMed2005

Neutrophils and the kallikrein-kinin system in proteinase-activated receptor 4-mediated inflammation in rodents.

1 We evaluated a potential role for proteinase-activated receptor 4 (PAR(4)) in a rodent paw inflammation model, with a focus on two main features of inflammation: (1) oedema and (2) granulocyte recruitment. 2 A PAR(4) antagonist (Pepducin P4pal-10; palmitoyl-SGRRYGHALR-NH(2)) reduced both the oedema and granulocyte recruitment induced by a localized administration of carrageenan in the rat hind paw, pointing to a key role for PAR(4) in this inflammation model. 3 Further, intraplantar injection in the mouse hind paw of a PAR(4) agonist (AYPGKF-NH(2)), but not its standard PAR(4)-inactive peptide control (YAPGKF-NH(2)), caused an inflammatory reaction characterized by oedema (increased paw thickness) and granulocyte recruitment (increased paw myeloperoxidase activity). The PAR(4) agonist-induced effects were inhibited in mice pretreated with pepducin P4pal10. 4 These PAR(4) agonist-mediated effects were not affected by pretreatment with inhibitors of either NO production or prostaglandin release (L-NAME and indomethacin, respectively). 5 However, selective immuno-depletion of neutrophils significantly reduced PAR(4) agonist-induced oedema formation. 6 Moreover, AYPGKF-NH(2)-induced oedema was also reduced by pretreatment with either a kinin B(2) receptor antagonist (icatibant) or a tissue or plasma kallikrein inhibitor (FE999024 and FE999026, respectively), but not with a kinin B(1) receptor antagonist (SSR240612). 7 We conclude: (1) that PAR(4) plays an important role in the inflammatory response as it mediates some of the hallmarks of inflammation and (2) that PAR(4)-mediated oedema is dependent on the recruitment of neutrophils and components of the kallikrein-kinin system.

Animals↗
PubMed2006

Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation.

OBJECTIVE: After activation, platelets expose CD40 ligand (CD40L) on their surface, then subsequently release the inflammatory mediator as a soluble fragment (sCD40L). Because sickle cell anemia (SCA) is noted for both platelet activation and chronic inflammation, we asked whether platelet-released CD40L potentially plays a role in SCA. METHODS AND RESULTS: ELISAs demonstrate that SCA patient plasma contains 30-fold more sCD40L than control plasma. Correspondingly, platelets from these patients contain less than half the CD40L found in control platelets. Platelets from patients in painful crises are further depleted of CD40L, with even higher plasma levels, suggesting a correlation to the patient's clinical state. In addition, elevated sCD40L correlates with increased tissue factor in SCA plasma. Blockage of the CD40L receptor CD40 reduces SCA plasma-induced production of tissue factor and endothelial intercellular adhesion molecule-1 (ICAM-1). Finally, sCD40L activity in SCA plasma is confirmed by its induction of B-cell proliferation. CONCLUSIONS: Platelet-derived sCD40L is elevated in SCA, further elevated in crises, and biologically active. The participation of sCD40L in SCA plasma-induced production of B cells, tissue factor, and ICAM-1 suggests that CD40L may contribute to the chronic inflammation and increased thrombotic activity known to occur in SCA.

Adult↗
PubMed2005

Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue.

Human adipose tissue is a contributor to inflammation- and sepsis-induced elevation of serum procalcitonin (ProCT). Several calcitonin (CT) peptides, including ProCT, CT gene-related peptide (CGRP), and adrenomedullin (ADM) are suspected mediators in human inflammatory diseases. Therefore, we aimed to explore the expression, interactions, and potential roles of adipocyte-derived CT peptide production. Expression of CT peptide-specific transcripts was analyzed by RT-PCR and quantitative real-time PCR in human adipose tissue biopsies and three different inflammation-challenged human adipocyte models. ProCT, CGRP, and ADM secretions were assessed by immunological methods. Adipocyte transcriptional activity, glycerol release, and insulin-mediated glucose transport were studied after exogenous CGRP and ADM exposure. With the exception of amylin, CT peptides were expressed in adipose tissue biopsies from septic patients, inflammation-activated mature explanted adipocytes, and macrophage-activated preadipocyte-derived adipocytes. ProCT and CGRP productions were significantly augmented in IL-1beta and lipopolysaccharide-challenged mesenchymal stem cell-derived adipocytes but not in undifferentiated mesenchymal stem cells. In contrast, ADM expression occurred before and after adipogenic differentiation. Interferon-gamma coadministration inhibited IL-1beta-mediated ProCT and CGRP secretion by 78 and 34%, respectively but augmented IL-1beta-mediated ADM secretion by 50%. Exogenous CGRP and ADM administration induced CT, CGRP I, and CGRP II mRNAs and dose-dependently (10(-10) and 10(-6) m) enhanced glycerol release. In contrast, no CGRP- and ADM-mediated effects were noted on ADM, TNFalpha, and IL-1beta mRNA abundances. In summary, CGRP and ADM are two differentially regulated novel adipose tissue secretion factors exerting autocrine/paracrine roles. Their lipolytic effect (glycerol release) suggests a metabolic role in adipocytes during inflammation.

Adipocytes↗
PubMed2005

Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK/STAT/SOCS signaling circuits in the CNS.

Cytokines are plurifunctional mediators of cellular communication. The CNS biology of this family of molecules has been explored by transgenic approaches that targeted the expression of individual cytokine genes to specific cells in the CNS of mice. Such transgenic animals exhibit wide-ranging structural and functional alterations that are linked to the development of distinct neuroinflammatory responses and gene expression profiles specific for each cytokine. The unique actions of individual cytokines result from the activation of specific receptor-coupled cellular signal transduction pathways such as the JAK/STAT tyrosine kinase signaling cascade. The cerebral expression of various STATs, their activation, as well as that of the major physiological inhibitors of this pathway, SOCS1 and SOCS3, is highly regulated in a stimulus- and cell-specific fashion. The role of the key IFN signaling molecules STAT1 or STAT2 was studied in transgenic mice (termed GIFN) with astrocyte-production of IFN-alpha that were null or haploinsufficient for these STAT genes. Surprisingly, these animals developed either more severe and accelerated neurodegeneration with calcification and inflammation (GIFN/STAT1 deficient) or severe immunoinflammation and medulloblastoma (GIFN/STAT2 deficient). STAT dysregulation may result in a signal switch phenomenon in which one cytokine acquires the apparent function of an entirely different cytokine. Therefore, for cytokines such as the IFNs, the receptor-coupled signaling process is complex, involving the coexistence of multiple JAK/STAT as well as alternative pathways. The cellular compartmentalization and balance in the activity of these pathways ultimately determines the repertoire and nature of CNS cytokine actions.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Early T cell response to allografts occurring prior to alloantigen priming up-regulates innate-mediated inflammation and graft necrosis.

The early inflammatory response within organ allografts is initiated by ischemia/reperfusion (I/R) and promotes subsequent alloantigen-primed T cell recruitment into and rejection of the graft. Polymorphonuclear leukocyte (PMN)-mediated tissue damage is a primary component of the early inflammation in allograft rejection. We sought to compare and elucidate the mechanism of early PMN infiltration into cardiac isografts and allografts. Despite identical production of PMN attractant chemokines, PMN infiltration following reperfusion into syngeneic and allogeneic grafts was not equivalent. PMN infiltration into isografts peaked at 9 to 12 hours post-transplant and quickly resolved. In contrast, PMN infiltration into allografts continued to elevated levels, peaking at 24 hours post-reperfusion. This amplified PMN infiltration into allografts did not resolve until 72 hours post-reperfusion and was accompanied by marked parenchymal necrosis. This early innate inflammatory response was regulated by IFN-gamma-producing CD8+ T cells present in the recipient before detectable alloantigen T cell priming. Co-culture with CD62L(low) CD8+ T cells, but not CD62L(high) CD8+ or CD62L(low) CD4+ T cells, harvested from naïve animals induced allogeneic endothelial cells to express IFN-gamma-dependent chemokines. These data demonstrate CD8+ T cell-mediated attack on the vascular endothelium of allografts within hours following organ reperfusion that amplifies innate immune-mediated intra-graft inflammation and necrosis.

Animals↗
PubMed2003

Interleukin-7-mediated inflammation in unstable angina: possible role of chemokines and platelets.

BACKGROUND: Atherogenesis and plaque destabilization involve immune-mediated mechanisms, but the actual mediators have not been fully clarified. Interleukin (IL)-7 is a regulator of T-cell homeostasis but also may be involved in inflammation. We hypothesized that IL-7 could be involved in the inflammatory processes observed in atherosclerosis and acute coronary syndromes. METHODS AND RESULTS: To study the role of IL-7 in coronary artery disease, we analyzed IL-7 levels and the effect of this cytokine on inflammatory mediators in patients with stable and unstable angina and in healthy control subjects. Our major findings were (1) Plasma levels of IL-7 were significantly increased in patients with stable (n=30) and unstable angina (n=30) comparing healthy control subjects (n=20), particularly in those with unstable disease. (2) Increased release from activated platelets appeared to be a major contributor to the raised IL-7 levels in patients with angina. (3) IL-7 enhanced the expression of several inflammatory chemokines in peripheral blood mononuclear cells from both healthy control subjects and patients with angina, particularly in those with unstable disease. Similar effects were seen in monocytes but not in T cells. (4) MIP-1alpha further increased the release of IL-7 from platelets in a dose-dependent manner. (5) Aspirin reduced both the spontaneous and the SFLLRN-stimulated release of IL-7 from platelets, and when administered to healthy control subjects for 7 days (160 mg qd), it reduced plasma levels of IL-7. CONCLUSIONS: Our findings suggest a role for IL-7-driven inflammation in atherogenesis and the promotion of clinical instability in coronary artery disease involving interactions between platelets, monocytes, and chemokines.

Angina, Unstable↗
PubMed2004

Triptolide, a Chinese herbal extract, protects dopaminergic neurons from inflammation-mediated damage through inhibition of microglial activation.

Mounting lines of evidence have suggested that brain inflammation participates in the pathogenesis of Parkinson's disease. Triptolide is one of the major active components of Chinese herb Tripterygium wilfordii Hook F, which possesses potent anti-inflammatory and immunosuppressive properties. We found that triptolide concentration-dependently attenuated the lipopolysaccharide (LPS)-induced decrease in [3H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in primary mesencephalic neuron/glia mixed culture. Triptolide also blocked LPS-induced activation of microglia and excessive production of TNFalpha and NO. Our data suggests that triptolide may protect dopaminergic neurons from LPS-induced injury and its efficiency in inhibiting microglia activation may underlie the mechanism.

Analysis of Variance↗
PubMed2005

Inflammation-mediated hyperexcitability of sensory neurons.

One of the most prominent signs of tissue injury and inflammation is pain and pain continues to be the primary reason people seek medical attention. Inflammatory pain reflects, at least in part, an increase in the excitability, or sensitization, of subpopulations of primary afferent neurons. While the sensitization of high threshold afferents was observed almost 40 years ago, the basis for this phenomenon continues to be an active and fertile area of research today. This review will summarize recent advances in our mechanistic understanding of sensitization, focusing on four general areas where re search has been most active or productive. These include: (1) the characterization of second messenger pathways underlying inflammation-induced changes in afferent excitability; (2) the impact of previous injury on the afferent response to subsequent inflammation; (3) the impact of target of innervation on the specific afferent response to inflammation, and (4) the impact of sex hormones on the sensitization of high threshold afferents. Work in these areas highlights how much has been learned about this process as well as how much there is yet to learn.

Afferent Pathways↗
PubMed2000

A humanized monoclonal antibody against respiratory syncytial virus (palivizumab) inhibits RSV-induced neurogenic-mediated inflammation in rat airways.

Respiratory syncytial virus (RSV) is the most important respiratory pathogen in infancy and early childhood and may predispose to subsequent lower respiratory tract illness. Recent data indicate that RSV up-regulates the substance P receptor, making the airways abnormally susceptible to the proinflammatory effects of this peptide released from sensory nerves. The present study was designed to determine whether the administration of RSV antibodies prevents the potentiation of neurogenic inflammation in rat airways. Five days after inoculation, sensory nerve-mediated extravasation of Evans blue-labeled albumin was significantly greater in the airways of RSV-infected rats than in pathogen-free controls. Polyclonal immune globulin enriched for RSV-neutralizing antibodies (RSVIG) reduced neurogenic extravasation when injected 24 h before intranasal inoculation of the virus but not when injected before endotracheal inoculation. A humanized MAb against RSV fusion protein (palivizumab) was twice as potent as RSVIG when given before intranasal inoculation and also caused significant inhibition after endotracheal inoculation. Furthermore, palivizumab inhibited neurogenic inflammation in RSV-infected rats when given 72 h after virus inoculation. These data suggest that palivizumab protects the respiratory tract from RSV-induced inflammation when given before or in the early phase of the viral infection. The administration of palivizumab to high-risk infants may limit the severity of the acute airway inflammation and may protect against subsequent lower respiratory tract illness.

Animals↗
PubMed2026

Targeted Epigenetic Silencing of Jumonji Domain-Containing Protein 3 Alleviates Nuclear Factor-Kappa B-Mediated Inflammation in Familial Mediterranean Fever.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory condition caused by variants in the MEFV gene encoding pyrin, the essential component of the NLRP3/NF-κB complex of inflammasomes. Deregulation of nuclear factor-kappa B (NF-κB), a key proinflammatory mediator, leads to chronic inflammation in autoinflammatory/autoimmune diseases. Epigenetic modulation offers a new approach to regulate inflammasome activity, with Jumonji domain-containing protein 3 (JMJD3) being a promising target for managing inflammatory illnesses. GSK-J4 is a selective inhibitor of JMJD3, restricting pro-inflammatory cytokines and inflammation. AIM: Our research aimed to elucidate the role of JMJD3 and the NF-κB-JMJD3 signaling pathways in regulating inflammation in an in vitro model, and to investigate GSK-J4's effect in inhibiting inflammasome activation in primed peripheral blood mononuclear cells (PBMCs) isolated from FMF cases. METHODS: PBMCs were cultured and primed with LPS, and then treated with GSK-J4. JMJD3 knockdown was achieved using siRNA interference. Cellular inflammatory dynamics were assessed by Western blotting (WB) and ELISA. The qRT-PCR was used for gene expression quantification. Untreated cells served as a negative control. RESULTS: Our results showed significantly downregulated gene expression of NF-κB, NLRP3, and inflammatory cytokines in GSK-J4-treated cells compared to untreated cells, as confirmed by ELISA. WB reported a reduction of NF-κB in induced cells following GSK-J4 treatment. Knocking down JMJD3 also showed decreased levels of JMJD3, NF-κB, and inflammatory cytokines, indicating its proinflammatory role. CONCLUSION: The study showed that selective inhibition or silencing of JMJD3 significantly suppressed the inflammasome in FMF cases, suggesting its role as a therapeutic target for alleviating inflammation in various autoinflammatory diseases.

Humans↗
PubMed1989

Urate-mediated inflammation in nodal osteoarthritis: clinical and roentgenographic correlations.

We studied 25 patients with crystal-proven gout or roentgenographic evidence of gouty arthritis, or both, in finger joints involved with nodal osteoarthritis (OA). These patients were elderly (mean age 71.4 years), and 72% of them were receiving diuretic therapy. Roentgenographic findings, in addition to features typical of OA, included soft tissue densities (tophi), with or without calcification, large intraarticular erosions, characteristic nonmarginal cortical erosions, and periarticular osteolysis. We conclude that urate crystals mediate episodes of acute inflammation in certain patients with nodal OA. This association is noted primarily in elderly patients of both sexes, especially in those receiving diuretic therapy.

Acute Disease↗
PubMed2000

Molecular mechanism of monocyte predominant infiltration in chronic inflammation: mediation by a novel monocyte chemotactic factor, S19 ribosomal protein dimer.

A novel monocyte chemotactic factor, a cross-linked homodimer of S19 ribosomal protein (RP S19) was initially isolated from a rheumatoid arthritis synovial lesion. The RP S19 dimer causes the monocyte specific chemotaxis in vitro and the monocyte predominant infiltration in vivo, via its agonistic and antagonistic effects on the C5a receptors of monocytes and polymorphonuclear leukocytes, respectively. The agonistic effect is attributed to the similarity of regional structures between RP S19 and C5a, the complement C5-derived leukocyte chemotactic factor, although overall homology of the amino acid sequence between these molecules is only 4%. The antagonistic effect depends upon the C-terminal portion of RP S19. The RP S19 dimer is produced and released by apoptotic cells, and this dimer recruits monocytes from the circulation to the apoptotic lesion. The infiltrated monocytes/macrophages engulf the apoptotic cells, translocate to regional lymph nodes via lymphatics and present the antigenic information of the apoptotic cells to the T cell repertoire. In this manner, the apoptotic cell clearance system connects to the acquired immune system. The innate and acquired immune mechanisms, mediated by the RP S19 dimer, participate in the pathology of inveterate chronic inflammation such as rheumatoid arthritis.

Amino Acid Sequence↗
PubMed2003

Mechanisms of inflammation-mediated airway smooth muscle plasticity and airways remodeling in asthma.

Recent evidence points to progressive structural change in the airway wall, driven by chronic local inflammation, as a fundamental component for development of irreversible airway hyperresponsiveness. Acute and chronic inflammation is orchestrated by cytokines from recruited inflammatory cells, airway myofibroblasts and myocytes. Airway myocytes exhibit functional plasticity in their capacity for contraction, proliferation, and synthesis of matrix protein and cytokines. This confers a principal role in driving different components of the airway remodeling process, and mediating constrictor hyperresponsiveness. Functional plasticity of airway smooth muscle (ASM) is regulated by an array of environmental cues, including cytokines, which mediate their effects through receptors and a number of intracellular signaling pathways. Despite numerous studies of the cellular effects of cytokines on cultured airway myocytes, few have identified how intracellular signaling pathways modulate or induce these cellular responses. This review summarizes current understanding of these concepts and presents a model for the effects of inflammatory mediators on functional plasticity of ASM in asthma.

Adaptation, Physiological↗
PubMed2004

The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing.

Cyclooxygenase-2 (COX-2) and the prostaglandin products generated as a result of COX-2 activity mediate a variety of biological and pathological processes. Scarless healing occurs in fetal skin in the first and second trimesters of development. This scarless healing process is known to proceed without a significant inflammatory response, which appears to be important for the lack of scarring. Because the COX-2 pathway is an integral component of inflammation, we investigated its role in the fetal repair process using a mouse model of scarless fetal wound healing. COX-2 expression in scarless and fibrotic fetal wounds was examined. In addition, the ability of exogenous prostaglandin E(2) to alter scarless fetal healing was evaluated. The results suggest that the COX-2 pathway is involved in scar production in fetal skin and that targeting COX-2 may be useful for limiting scar formation in adult skin.

Animals↗
PubMed2000

Kinetics of cells and cytokines during immune-mediated inflammation in the mammary gland of cows systemically immunized with Staphylococcus aureus alpha-toxin.

OBJECTIVE: To examine changes in inflammatory mediators, lymphocyte subpopulations and neutrophil activation that occur during an immune-mediated recruitment of neutrophils in the mammary gland. SUBJECTS: 11 clinically healthy cows. TREATMENT: 5 cows received 2 subcutaneous injections of 30 microg of alpha-toxin of Staphylococcus aureus, two months apart. Three months after the last immunization, 5 microg of alpha-toxin were injected, via the teat end, in one randomly selected quarter of the 5 immunized cows and of the 6 unimmunized cows (control group). METHODS: Blood and milk samples were collected at several times during 4 days post-challenge. Blood and milk cells were purified to be stained with specific mAbs and analysed by flow cytometry, or to be used for cytokine RT-PCR. Bovine serum albumin, haptoglobin, cytokines and C5a were also analysed in milk or plasma samples using radial immunodiffusion assay or ELISA. RESULTS: Large amounts of cells (> 1 million/ml of milk) were recruited in the quarters of the immunized cows, whereas no recruitment occurred in the control group. In blood of immunized animals, haptoglobin was present and expression of surface adhesion molecules on neutrophils was modified whereas no change was observed concerning the lymphocyte subpopulations. On milk-derived neutrophils, the expression of CD11b and CD18 was upregulated compared to blood, in contrast to CD62L that was downregulated. The CD8+ cells were recruited as soon as 12 h post-challenge, in contrast to the CD4+ cells, 96 h post-challenge. No IL-1beta, TNF-alpha, IL-8 and C5a were detected using ELISA. mRNA of IL-1alpha, IL-1beta, IL-6, TNF-alpha, IL-8 and IL-12 were found in almost all the samples. CONCLUSIONS: The immunization triggered an early and massive neutrophil recruitment from the blood into the milk compartment as well as the recruitment of a cytotoxic/suppressor lyphocyte population during the early acute phase response. These results could help to devise new vaccinal strategies to fight against staphylococcal mastitis.

Animals↗